US8258148B2ExpiredUtilityPatentIndex 49
Spiroindoline modulators of muscarinic receptors
Est. expiryAug 19, 2024(expired)· nominal 20-yr term from priority
Inventors:MAKINGS LEWIS RBLANCO MIGUEL GARCIA-GUZMANHURLEY DENNIS JDRUTU IOANARAFFAI GABRIELBERGERON DANIELE MNAKATANI AKIKOTERMIN ANDREAS PSILINA ALINA
A61P 9/06A61P 43/00A61P 9/00A61P 3/10A61P 27/02A61P 25/14A61P 25/28A61P 25/24A61P 25/18A61P 25/00A61P 25/04A61P 3/04A61P 25/22A61P 27/06A61P 25/16C07D 405/04C07D 451/04C07D 451/02C07D 471/10A61K 31/4747C07D 223/32A61K 31/435C07D 405/12C07D 405/06C07D 401/06C07D 491/10A61K 31/55A61K 31/438A61P 17/02A61P 11/06A61P 1/04C07D 221/20A61P 1/02C07D 223/14
49
PatentIndex Score
0
Cited by
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References
29
Claims
Abstract
The present invention relates to spiroindoline modulators of muscarinic receptors. The present invention also provides compositions comprising such spiroindoline modulators, and methods therewith for treating muscarinic receptor mediated diseases.
Claims
exact text as granted — not AI-modified1. A method of modulating activity of an M 1 or M 4 muscarinic receptor, comprising the step of contacting said receptor with a compound of formula (I)
or pharmaceutically acceptable salts thereof, wherein
Each of R 1 , R 2 , R 3 is independently Q 1 or Q 2 ;
Z 1 is —N(Q 1 )- or —N(Q 2 )-;
Z 2 is N;
L is a bond, an aliphatic group, C 3 -C 6 cycloaliphatic, —O—, —S(O) z —, —S(O) z —(C 1 -C 4 )alkyl-, or —S(O) z N(Q 2 )-, in which the aliphatic group is optionally substituted with 1-3 of oxo, Q 1 , or Q 2 ;
G is a monocycloheteroaliphatic group, selected from pyrrolidine, piperidine and azepane, or G is an adamantyl, or a bicyclic or a tricyclic group of the formula (III)
in which the monocycloheteroaliphatic group, the adamantyl, and the bicyclic or tricyclic group are connected to L via any ring atom including those in X 1 and ring B, and the monocycloheteroaliphatic, the bicyclic, and the tricyclic groups are optionally substituted with 1-3 of oxo, ═N—OQ 4 , fluorine, Q 2 , —C(O)—X 2 -aliphatic in which X 2 is absent, —O—, —NH—, —NQ 2 -, or —S(O) z — and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 ;
Bond r is a single or double bond and when ring B is present, bond r is fused with B;
Ring B, when present, is a 5-6 membered cycloaliphatic or heterocycloaliphatic ring, and is optionally substituted with 1-3 of oxo, Q 1 , or Q 2 ;
X 1 is —(CH 2 ) i —, —O—, —S—, —N(Q 2 )-, or —N(—C(O)—X 2 -aliphatic) in which X 2 is absent, —O—, —NH—, —NQ 2 -, or —S(O) z — and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 ;
Each Q 1 is independently halo, —CN, —NO 2 , —OQ 2 , —S(O) z Q 2 , —S(O) z N(Q 2 ) 2 , —N(Q 2 ) 2 , —C(O)OQ 2 , —C(O)-Q 2 , —C(O)N(Q 2 ) 2 , —C(O)N(Q 2 )(OQ 2 ), —N(Q 2 )C(O)-Q 2 , —N(Q 2 )C(O)N(Q 2 ) 2 , —N(Q 2 )C(O)O-Q 2 , —N(Q 2 )S(O) z -Q 2 or aliphatic optionally including 1-3 substituents independently selected from Q 2 or Q 3 ;
Each Q 2 is independently H, aliphatic, cycloaliphatic, aryl, arylalkyl, heterocyclic, or heteroaryl ring, each optionally including 1-3 substituents independently selected from Q 3 ;
Each Q 3 is halo, oxo, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH, —S(O) z Q 4 , —N(Q 4 ) 2 , —COOQ 4 , —C(O)Q 4 , —OQ 4 , or C 1 -C 4 alkyl optionally substituted with halo, oxo, —CN, —NO 2 , —CF 3 , —OCF 3 , —OH, —SH, —S(O) z H, —NH 2 , or —COOH;
Each Q 4 is aliphatic, cycloaliphatic, aryl, aralkyl, heterocycloaliphatic, heteroaralky, or heteroaryl, each optionally including 1-3 substituents selected from halo, oxo, CN, NO 2 , CF 3 , OCF 3 , OH, SH, —S(O) z H, —NH 2 , or COOH;
Each Q 5 is a heterocyclic ring optionally including 1-3 substituents selected from halo, C 1 -C 4 alkyl, oxo, CN, NO 2 , CF 3 , OCF 3 , OH, SH, —S(O) z H, —NH 2 , COOH;
Each i is independently 1, 2, or 3;
Each m and n is 2;
Each p is 0;
Each y is independently 0 or 1;
Each t is 1 to 4; and
Each z is independently 0, 1, or 2.
2. The method of claim 1 , wherein G is substituted with alkyl, aryl, haloalkyl, alkoxycarbonyl, or alkoxyamino.
3. The method of claim 1 , wherein G is an optionally substituted 5 to 7 membered monoheterocycloaliphatic group selected from pyrrolidine, piperidine and azepane.
4. The method of claim 3 , wherein G is substituted with 1 to 2 substituents independently selected from Q 2 , and —C(O)—X 2 -aliphatic, where X 2 is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 .
5. The method of claim 3 , wherein G is substituted with 1 to 2 substituents independently selected from alkoxycarbonyl, alkynyloxycarbonyl, alkoxyalkoxycarbonyl, haloalkoxycarbonyl, heterocycloalkoxycarbonyl, and cycloalkoxycarbonyl.
6. The method of claim 1 , wherein G is one selected from
7. The method of claim 1 , wherein G is an optionally substituted bicyclic group of formula (III) in which ring B is absent.
8. The method of claim 7 , wherein X 1 is —(CH 2 ) i .
9. The method of claim 8 , wherein G is optionally substituted bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.1]heptanyl.
10. The method of claim 9 , wherein G is substituted with 1 to 2 substituents independently selected from Q 2 , and —C(O)—X 2 -aliphatic, where X 2 is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 .
11. The method of claim 7 , wherein X 1 is —N(Q 2 )- or —N(C(O)—X 2 -aliphatic)-, where X 2 is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 .
12. The method of claim 11 , wherein G is an optionally substituted tropane.
13. The method of claim 12 , wherein the tropane is substituted with Q 2 or —C(O)—X 2 -aliphatic, where X 2 is absent, —O—, —NH—, or —NQ 2 -, and the aliphatic group is optionally substituted with 1-3 substituents independently selected from Q 3 .
14. The method of claim 13 , wherein the tropane is substituted at the tropane ring nitrogen atom with alkoxycarbonyl, alkoxyalkoxycarbonyl, heterocycloalkoxycarbonyl, cycloalkoxycarbonyl, alkoxyaryloxycarbonyl, alkylaminocarbonyl, haloalkoxycarbonyl, alkynyloxycarbonyl, or heterocycloalkylalkoxycarbonyl.
15. The method of claim 14 , wherein G is selected from
16. The method of claim 1 , wherein Z 1 is —NH—, or —N(Q 1 )-.
17. The method of claim 16 , wherein Z 1 is —N(Q 1 )- and Q 1 is alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonylamino, aminocarbonyl, alkylcarbonylalkyl, alkoxyalkoxycarbonyl, alkoxyalkyl, alkylaminocarbonyl, alkoxycarbonyl, haloarylcarbonyl, haloarylsulfonyl, alkylheteroarylcarbonyl, heteroarylcarbonyl, heterocycloalkylcarbonyl, haloarylaminocarbonyl, alkylheteroarylsulfonyl, cyanoalkylarylcarbonyl, heterocycloalkoxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, heterobicycloarylcarbonyl, alkylheteroarylaminocarbonyl, alkylsulfonyl, alkylcarbonylalkyl, alkoxyarylcarbonyl, haloalkoxycarbonyl, alkylarylcarbonyl, haloalkoxyarylcarbonyl, or arylaminocarbonyl.
18. The method of claim 16 , wherein Z 1 is one selected from —NH—,
19. The method of claim 1 , wherein R 1 is selected from hydrogen, halo, or optionally substituted alkyl, heteroaryl, alkoxy, alkenyl, cycloalkyl, cyanoalkylaryl, alkylaryl, alkylsulfonylaryl, alkylcarbonylaryl, aryl, aminocarbonylaryl, alkylcarbonylaminoaryl, cycloalkenyl, and alkoxyaryl.
20. The method of claim 19 , wherein R 1 is selected from hydrogen, halo, methyl,
21. The method of claim 1 , wherein R 2 and R 3 are independently hydrogen or alkyl.
22. The method of claim 21 , wherein R 2 and R 3 are both hydrogen.
23. The method of claim 1 , wherein L is a bond or an aliphatic group optionally substituted with 1-3 of oxo, Q 1 , or Q 2 .
24. The method of claim 23 , wherein L is a bond.
25. The method of claim 23 , wherein L is —CH 2 —.
26. A method of treating or reducing the severity of a disease or condition in a patient, wherein said disease or condition is selected from pain, schizophrenia, Parkinson's disease, glaucoma, or Attention Deficit Hyperactivity Disorder (ADHD), wherein said method comprises the step of contacting said patient with a compound as described in of claim 1 .
27. A method of modulating activity of an M 1 or M 4 muscarinic receptor, comprising the step of contacting said receptor with a compound selected from:
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28. The method of claim 26 , wherein the disease or condition is selected from Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia, Parkinson's disease and Glaucoma.
29. The method of claim 26 , wherein the disease or condition is pain.Cited by (0)
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